Protocol of a prospective study on the diagnostic value of transcranial duplex scanning of the substantia nigra in patients with parkinsonian symptoms

Background  

Parkinson's disease (PD) is the second most common neurodegenerative disorder. As there is no definitive diagnostic test, its diagnosis is based on clinical criteria. Recently transcranial duplex scanning (TCD) of the substantia nigra in the brainstem has been proposed as an instrument to diagnose PD. We and others have found that TCD scanning of substantia nigra duplex is a relatively accurate diagnostic instrument in patients with parkinsonian symptoms. However, all studies on TCD so far have involved well-defined, later-stage PD patients, which will obviously lead to an overestimate of the diagnostic accuracy of TCD.     

Reversible cell cycle inhibition and premature aging features imposed by conditional expression of p16Ink4a

The cyclin‐dependent kinase (Cdk) inhibitor p16^Ink4a (p16) is a canonical mediator of cellular senescence and accumulates in aging tissues, where it constrains proliferation of some progenitor cells. However, whether p16 induction in tissues is sufficient to inhibit cell proliferation, mediate senescence, and/or impose aging features has remained unclear. To address these issues, we generated transgenic mice that permit conditional p16 expression. Broad induction at weaning inhibited proliferation of intestinal transit‐amplifying and Lgr5+ stem cells and rapidly imposed features of aging, including hair loss, skin wrinkling, reduced body weight and subcutaneous fat, an increased myeloid fraction in peripheral blood, poor dentition, and cataracts. Aging features were observed with multiple combinations of p16 transgenes and transactivators and were largely abrogated by a germline Cdk4 R24C mutation, confirming that they reflect Cdk inhibition. Senescence markers were not found, and de‐induction of p16, even after weeks of sustained expression, allowed rapid recovery of intestinal cell proliferation and reversal of aging features in most mice. These results suggest that p16‐mediated inhibition of Cdk activity is sufficient to inhibit cell proliferation and impose aging features in somatic tissues of mammals and that at least some of these aging features are reversible.     

Effects of aerobic exercise therapy and cognitive behavioural therapy on functioning and quality of life in amyotrophic lateral sclerosis: protocol of the FACTS-2-ALS trial

Background

Neuropathic pain must be correctly diagnosed for optimal treatment. The questionnaire named Neuropathic Pain Symptom Inventory (NPSI) was developed in its original French version to evaluate the different symptoms of neuropathic pain. We hypothesized that the NPSI might also be used to differentiate neuropathic from non-neuropathic pain.

Methods

We translated the NPSI into German using a standard forward-backward translation and administered it in a case-control design to patients with neuropathic (n = 68) and non-neuropathic pain (headache and osteoarthritis, n = 169) to validate it and to analyze its discriminant properties, its sensitivity to change, and to detect neuropathic pain subgroups with distinct profiles.

Results

Using a sum score (the NPSI-G score), we found sensitivity to change (r between 0.37 and 0.5 for pain items of the graded chronic pain scale) and could distinguish between neuropathic and other pain on a group basis, but not for individual patients. Post hoc development of a discriminant score with optimized diagnostic properties to distinguish neuropathic pain from non-neuropathic pain resulted in an instrument with high sensitivity (91%) and acceptable specificity (70%). We detected six different pain profiles in the patient group with neuropathic pain; three profiles were found to be distinct.

Conclusions

The NPSI-G potentially combines the properties of a diagnostic tool and an instrument to identify subtypes of neuropathic pain.     

Cell death induced by Pteris semipinnata L. is associated with p53 and oxidant stress in gastric cancer cells

In this study, we demonstrated that Ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F) had stronger cytotoxicity against MKN-45, a gastric cancer cell line bearing wild-type p53 than MKN-28, another gastric cancer cell line containing missense mutation in p53. The rapid increase of ROS level was involved in the mechanism of cytotoxicity. Classical features of apoptosis induced by 5F were observed in MKN-45 cells only or more significant in MKN-45 cells than MKN-28 cells. Translocation of Bax from cytosol to mitochondria, reduction of delta psi m and DNA fragmentation were induced by 5F in the p53-dependent manner. We conclude that the expression of Bax and its downstream molecules requires the presentation of a wild-type p53 in the cells treated by 5F.     

Effect of body mass and water temperature on the standard metabolic rate of juvenile yellow perch, Perca flavescens (Mitchill)

Fish respiration rates that are presumed to represent standard metabolic rates (SMR) may sometimes include an unspecified energy expenditure associated with activity and digestion. This situation may introduce a bias in bioenergetics models because standard metabolism, digestion, and activity may not be affected by the same environmental conditions. The aim of this study was to (1) develop a SMR model for juvenile yellow perch, Perca flavescens (Mitchill), that represent the minimum energy expenditure required to maintain life and (2) compare the results of this study with published perch metabolic rates and bioenergetics models. SMR was estimated for yellow perch over a range of body␣mass (4.4–24.7 g) and water temperature (12–20°C). The intercept of the relationship between fish respiration and swimming velocity obtained during forced swimming experiments was used to determine SMR. SMR estimated by the present study were comparable to values presented by two published studies on Eurasian perch, Perca fluviatilis L. However, estimated SMR were 4.1–20.9 times lower than values of a third respirometry study and predictions of bioenergetics models for perch. The present study suggests that published SMR models may sometimes include a significant fraction of energy expenditures (39.2–75.9%) associated with digestion and activity. This may complicate the implementation and the interpretation of fish bioenergetics models. The present study indicates that the intercept of respiration-velocity relationships and long-term respiration rates during starvation experiments may provide similar and reliable SMR values.     

A severe form of human combined immunodeficiency due to mutations in DNA ligase IV

DNA ligase IV (LigIV) deficiency was identified as the molecular basis for a severe form of combined immunodeficiency in two microcephalic siblings with cellular radiosensitivity. In one patient the diagnosis was made directly after birth, allowing analysis of the role of LigIV in the development of specific immune cells. Absolute numbers of B cells were reduced 100-fold and alphabeta T cells 10-fold, whereas gammadelta T cells were normal. Spectratyping of all three cell populations showed a diverse repertoire, but sequencing of IgH V(D)J junctions revealed shorter CDR3 regions due to more extensive nucleotide deletions among D and J elements and fewer N nucleotide insertions. Clonal restriction of IgG-expressing, but not IgM-expressing, B cells and the lack of primary and secondary lymph node follicles indicated impaired class switch recombination. Observations in the older sibling showed that this rudimentary immune system was able to mount specific responses to infection. However, partial Ab responses and extensive amplification of gammadelta T cells could not prevent a life-threatening course of viral and bacterial infections, the development of an EBV-induced lymphoma, and immune dysregulation reflected by severe autoimmune cytopenia. Impaired generation of immune diversity under conditions of limited LigIV activity can cause a human SCID variant with a characteristic immunological phenotype.     

De novostructural chromosomal imbalances: molecular cytogenetic characterization of partial trisomies

De novo structural chromosomal imbalances represent a major challenge in modern cytogenetic diagnostics. Based solely on conventional cytogenetic techniques it may be impossible to identify the chromosomal origin of additional chromosomal material. In these cases molecular cytogenetic investigations including multicolor-FISH (M-FISH), spectral karyotyping (SKY), multicolor banding (MCB) and cenM-FISH combined with appropriate single-locus FISH probes are highly suitable for the determination of the chromosomal origin and fine characterization of derivative chromosomes. Here we report on four patients with de novo chromosomal imbalances and distinct chromosomal phenotypes, three of them harboring pure partial trisomies: a mildly affected boy with pure partial trisomy 10q22.2-->q22.3 approximately 23.1 due to an interstitial duplication, a girl with pure trisomy 12p11.21-->pter and atypically moderate phenotype as the consequence of an X;autosome translocation, and a girl with multiple congenital abnormalities and severe developmental delay and a 46,XX,15p+ karyotype hiding a trisomy 17pter-->17q11.1. The fourth patient is a girl with minor phenotypic features and mental retardation with an inverted duplication 18q10-->p11.31 combined with a terminal deletion of 18p32. The clinical pictures are compared with previously described patients with focus on long term outcome.     

Zebrafish transgenic Enhancer TRAP line database (ZETRAP)

Background  

The zebrafish, Danio rerio, is used as a model organism to study vertebrate genetics and development. An effective enhancer trap (ET) in zebrafish using the Tol2 transposon has been demonstrated. This approach could be used to study embryogenesis of a vertebrate species in real time and with high resolution.     

A 47,XXY female with unusual genitalia

A 47,XXY karyotype was found in a 6-year-old girl. The patient had female external genitalia, clitoromegaly, remnants of the ductus mesonephricus, uterus, and gonads in the labia majora which were determined to be testes by histology. Cytogenetic and DNA analyses suggest that the Y chromosome had a normal structure and that both X chromosomes were of maternal origin. The unusual clinical findings in the patient are discussed.Dedicated to Professor Ulrich Wolf on the occasion of his 60th birthday